This proposal will develop potential PET ligands for each of the three opioid receptors. In this project the target compounds will be synthesized, with pharmacological evaluation of the cold ligands carried out in Project 2. For promising compounds, their appropriate precursors will be synthesized and provided to Project lb for radiolabeling and further evaluation. The development of such compounds will significantly improve our ability to define the function of the opioid system in dependent and non-dependent individuals. A potential ligand will also be made for the more recently discovered ORL-1 receptor. Further work will explore the structural motifs that determine the pharmacological profile, and in particular irreversible mu-binding, of C-CAM and close analogues. This will include the development of alternative, synthetically more accessible series and also alternatives to buprenorphine for the treatment of heroin abuse. This project will also provide compounds that are unavailable, or prohibitively expensive for the Center group for primate studies.